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within a cluster could work in an antagonizing, rather than cooperative, manner. Similarly, miR-146a
deficient mice have been shown to display increased airway inflammation and type 2 immune response in
[38]
a mouse model of house dust mite (HDM)-induced asthma . Indeed, a polymorphism in miR-146a was
[39]
found to be associated with human asthma .
Another potentially inhibitory group of miRNAs is the let-7 family. These miRNAs act as regulators of IL-13
[40]
expression by direct targeting the 3’ UTR of the IL-13 transcript . Furthermore, induced levels of IL-13
in cultured T cells were shown to inversely correlate to let-7 levels. In a mouse model of allergic airway
inflammation, let-7 family members were down-regulated and intranasal administration of let-7 mimics
[41]
led to reduction of IL-13 expression and resolution of allergic airway inflammation . Although the two
[41]
research teams came to different conclusions regarding the role of let-7, Kumar et al. speculated where the
two studies may have differed from each other. First of all, differences in methodology may have led to some
discrepancies as the treatment route - systemic vs. local could have an impact on the efficacy of the miRNA.
Additionally, there may be a negative feedback loop with the miRNA processing enzyme Dicer, leading
to the anti-inflammatory effects of let-7 inhibition. Furthermore, in vitro data highlighted the complexity
of miRNAs as the endogenous abundance of different let-7 family members as well as the functional
redundancy of the IL-13 3’ UTR, likely played a role in the effectiveness of target binding and down-
[41]
regulation . However, in an additional study, let-7 inhibitors also decreased allergic airway inflammation;
thus, arguing for a complexity in the miRNAome in these models, and suggesting a pro-inflammatory role
[40]
of let-7 in allergic airway inflammation and asthma .

[42]
One of the most studied miRNAs is miR-155, which is highly conserved across metazoans . Earlier studies
of this miRNA showed that CD4+ T cells lacking miR-155 had a tendency to undergo spontaneous Th2
differentiation under normal conditions [43,44] . Indeed, overexpression of miR-155 in CD4+ T cells promoted
Th1 differentiation in vitro, suggesting a role for miR-155 in T cell polarization. In contrast to these studies,
we and others have shown that miR-155 promotes type 2 inflammation in vivo in models of allergic asthma,
suggesting a fine tuning, context dependent regulation by this miRNA. Indeed, miR-155 was significantly
upregulated in the lung of both acute and chronic models of allergic asthma [45,46] . Additionally, allergen
challenged miR-155 deficient mice had diminished Th2 responses and airway eosinophilia, which was
[46]
related to an increased expression of the transcription factor PU.1 in lung draining lymph nodes . Elevated
PU.1 is probably one reason for the suppressed Th2 responses in miR-155 deficient mice since PU.1 is both
a direct target of miR-155 and a negative regulator of GATA-3, an important transcription factor for Th2
cells. In addition, other in vivo studies have also demonstrated that miR-155 is required for type 2 immunity.
In a mouse model of HDM-induced asthma, miR-155 was shown to be required for HDM-induced hyper-
responsiveness and cell recruitment, mediated partially through direct targeting of sphingosine-1-phosphate
[38]
receptor 1 (Sp1r1) .
Specific miRNAs have been found to participate in polarization of adaptive type 2 immune responses. One
such miRNA is miR-21, which has been shown to be upregulated in models of allergic asthma. In particular,
[47]
miR-21 was shown to regulate the Th1 and Th2 balance by targeting IL-12p35 expression . Overexpression
of miR-21 promoted in vivo differentiation of Th2 cells. Furthermore, allergen-challenged miR-21 deficient
mice had reduced airway eosinophilia and decreased levels of Th2 cytokine, IL-4 with concomitant increased
levels of the Th1 cytokine, interferon (IFN)-gamma.

ILC2s
In addition to Th2 cells, the ILC2s also produce type 2 cytokines that drive allergic airway inflammation.
These cells respond to the epithelial derived cytokines IL-33, IL-25 and thymic stromal lymphopoietin and
have been suggested to play a significant role both in the initiation and the maintenance of chronic airway
inflammation [48,49] . Indeed, these cells have been shown to be present in sputum and in bronchoalveolar